Both clinical and electrophysiologic (VER waveform) ameliorations of hepatic encephalopathy (HE), have been induced in animals with FHF by benzodiazepine (BZ) receptor ligands with antagonist properties. Furthermore spontaneous in vitro activity of Purkinje neurons from rabbits in HE due to FHF exhibited increased sensitivity to depression by agonists of the GABA/BZ receptor complex, including a BZ, and in contrast to control neurons, exhibited excitation when exposed to BZ receptor antagonists. In addition a BZ receptor antagonist reversed the hypersensitivity of HE rabbit neurons to depression by a GABA agonist. The functional status of the chloride ionophore of the GABA/BZ receptor complex has been shown to be normal in rat model of HE due to FHF. Radioligand binding to BZ receptors, determined autoradiographically, was decreased in thin unwashed sections from HE rabbit brains. Purification and characterization of HE rat brain extracts revealed the presence of reversible, competitive, BZ receptor ligands with agonist properties. Two of the ligands have been chemically characterized as the 1,4-BZs diazepam and N-desmethyldiazepam. The concentrations of the compounds were 2-9 fold greater in HE rat brain than control brain. Overall, these findings suggest that in HE due to FHF: (i) There is increased GABA- ergic tone; (ii) Blockading of BZ receptors can ameliorate HE; (iii) BZ receptor antagonists may be of value in the management of HE; and (iv) Endogenous BZ receptor agonists probably contribute of HE. The efficacy of BZ receptor ligands in ameliorating HE in animal models does not appear to depend on their affinity for BZ receptor subtypes in addition to the diazepam sensitive receptor.